New Alzheimer's Drugs May Do the Opposite, and Impair Memory

Some new Alzheimer's drugs being tested may disrupt new forming axons from being correctly wired, and impair memory.
The axon bundles (green) of some of these neurons project toward the forebrain in the E16.5 mouse embryo. Immature dopamine neurons (red) and non-dopamine neurons of the midbrain are derived from the Shh lineage (purple).
Eunice Kennedy Shriver Nationa

Scientists who have discovered a new class of Alzheimer's disease drugs are now saying that the drugs compound’s molecular target, which is currently being tested in clinical trials, may actually have the opposite effect that could impair memory, according to a new study in animals.

The drugs are designed to inhibit BACE1 enzymes that promote the development of protein plaques, which are a hallmark of Alzheimer's disease. However, a new study with mice suggests that these drugs known as BACE1 inhibitors may interfere with the brain’s wiring and interfere with the ability of brain cells to form new memories.

Researchers explained that they had initially thought that blocking the BACE1 enzyme might slow the disease, but their latest studies indicated that blocking the enzyme also stopped it from executing a crucial neuron-mapping function in the brain which caused neurons to be improperly wired which interfered with their ability to send messages to the brain.

Investigators showed in their latest study that genetically engineered mice devoid of BACE1 had olfactory neurons, used for the sense of smell, were incorrectly wired to the olfactory bulb of the brain.

Northwestern University cell and molecular biologist Robert Vassar, who also led the original research on BACE1 inhibitors to treat Alzheimer's disease, explained that the BACE1 enzyme works like the brain’s electrician because has a critical role in mapping out the location of axons, wires that connect neurons to the brain and the rest of the nervous system.

Vassar said that the latest findings are worrying because it demonstrated the essential role of BACE1 in brain wiring for the olfactory system, which is a good model in other brain regions like the hippocampus, which could be particularly vulnerable to BACE1 blockers, because neurons in that region are continually being reborn, and may play a role in forming new memories. Neurons need to grow new axons to make new connections, which is why axonal guidance is a continuous need.

“Let’s proceed with caution,” he said Saturday at the annual meeting for the American Association for the Advancement of Science. “We have to keep our eyes open for potential side effects of these drugs.”

“It’s not all bad news,” Vassar added. “These BACE1 blockers might be useful at a specific dose that will reduce the amyloid plaques but not high enough to interfere with the wiring. Understanding the normal function of BACE1 may help us avoid potential drug side effects.

The findings are published in the journal Molecular Neurodegeneration.